The specific aims of this competitive renewal application are: (1) Completion of total synthesis of chlorothricolide and kijanolide. (2) Completion of a total synthesis of nargenicin A1, and synthesis of presumed nargenicin biosynthetic intermediates. (3) Stereostructure assignment and total synthesis of quartomicin D3, and synthesis of simpler quartromicin analogs. (4) Total synthesis of A835543A (lepicidin) via a transannular Diels-Alder reaction of an (E,E,E)- cyclododeca-1,7,9-triene. The central theme of this proposal is the development of highly stereoselective syntheses of biologically active natural products by routes involving intramolecular Diels-Alder (IMDA) reactions. Major sub- goals of this program are the development of strategies or methods for achieving high levels of stereochemical control i the IMDA reactions. The major focus of methodological studies that will be performed in the net grant period concerns use of conformational preferences of macrocylic systems to control the stereochemical course of transannular Diels-Alder reactions in the kijanolide, nargenicin, and lepicidin syntheses. As with previous contributions in methodology and total synthesis from this program, this research to be conducted in the next grant period should be of great assistance to organic, bioorganic and medicinal chemists involved with synthetic problems that fall outside the specific goals of this program. The targets for these investigations possess a range of interesting and significant biological properties. Chlorothricolide is the aglycone of an antibiotic with activity against gram-positive bacteria; kijanolide is the aglycone of kijanimicin that is active against an unusual range of microorganisms, including Plasmodium burgher and P. chabaudin (e.g., malaria); nargenicin is an antibiotic with significant antibacterial activity against Staphylococcus aureus and other gram-positive bacteria; the quartromicins exhibit excellent antiviral against herpes simplex virus type 1, influenza virus type A, and human immunodeficiency virus; and lepicidin is a very potent insecticidal agent that is particularly effective against instar mosquito larvae, and thus may be important in the control of malaria. In addition to these specific natural product targets, we plan to synthesize several compounds (118 and 119a,b) that are believed to be late stage intermediates in the nargenicin biosynthesis, as well as several quartromicin analogs (157, 158). If these analogs retain the anti-viral activity of the parent quartromicins, this will open up a more easily synthesized series for systematic analogs studies.